EP1100778B1 - Derives distamycine sulfures et oxydes, leur procede de preparation et utilisation en tant qu'agents antitumoraux - Google Patents

Derives distamycine sulfures et oxydes, leur procede de preparation et utilisation en tant qu'agents antitumoraux Download PDF

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EP1100778B1
EP1100778B1 EP99941465A EP99941465A EP1100778B1 EP 1100778 B1 EP1100778 B1 EP 1100778B1 EP 99941465 A EP99941465 A EP 99941465A EP 99941465 A EP99941465 A EP 99941465A EP 1100778 B1 EP1100778 B1 EP 1100778B1
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Prior art keywords
carboxamido
methyl
pyrrole
compound
chloroethylsulfinyl
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EP1100778A1 (fr
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Paolo Cozzi
Marina Caldarelli
Italo Beria
Maria Cristina Geroni
Laura Capolongo
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Pfizer Italia SRL
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Pharmacia Italia SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to new alkylating antitumor agents analogous to Distamycin A, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents.
  • Distamycin A whose formula is reported below belongs to the family of the pyrroleamidine antibiotics and it is reported to interact reversibly and selectively with DNA-AT sequences, thus interfering with both replication and transcription. See, for a reference, Nature, 203, 1064 (1964); FEBS Letters, 7 (1970) 90; Prog. Nucleic Acids Res. Mol, Biol., 15 , 285 (1975).
  • DE-A-1795539 discloses distamycin derivatives in which the formyl group is replaced by a hydrogen atom or by the carboxylic acid residue of a C 1 -C 4 aliphatic or cyclopentylpropionic acid.
  • EP-A-246,868 describes distamycin analogues in which the distamycin formyl group is substituted by aromatic, alicyclic or heterocyclic moieties bearing alkylating groups.
  • WO 97/28123 and WO 97/43258 describe distamycin analogues in which the amidino group is replaced with different nitrogen-containing ending groups and the distamycin formyl group is substituted by an aromatic or a cinnamoyl moiety, respectively.
  • distamycin derivatives as defined hereinunder, wherein the distamycin formyl group is substituted by a phenylcarbonyl, phenylalkylcarbonyl or phenylalkenylcarbonyl group bearing a haloethyl-sulfinyl or a haloethyl-sulfonyl group as an alkylating moiety, and the amidino group is optionally replaced by various nitrogen-containing ending groups, shows valuable biological properties.
  • the present invention provides compounds which are oxidised sulfurated distamycin derivatives of formula: wherein:
  • the present invention includes within its scope also all the possible isomers covered by the compounds of formula (I), both separately and in admixture, as well as the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).
  • alkyl and alkoxy include straight or branched C 1 -C 4 alkyl and alkoxy groups such as, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • Preferred C 1 -C 4 alkyl or alkoxy groups are methyl, ethyl, methoxy and ethoxy groups.
  • the C 1 -C 4 alkyl groups are preferably C 1 -C 4 perfluoroalkyl groups, e.g. trifluoromethyl.
  • alkylene and alkenylene refer, respectively, to C 1 -C 4 alkylene or C 2 -C 4 alkenylene groups, as bivalent radicals of the corresponding C 1 -C 4 saturated or C 2 -C 4 unsaturated hydrocarbons.
  • Preferred alkylene or alkenylene groups according to the present invention are methylene, ethylene or vinylene groups.
  • halogen atom includes fluorine, chlorine, bromine and iodine, being chlorine and bromine preferred.
  • the haloethyl-sulfinyl or sulfonyl group and the A group are in ortho, meta or para position with respect to each other; preferably, they are in meta or para position.
  • compositions of formula (I) are their salts with pharmaceutically acceptable either inorganic or organic acids such as, for instance, hydrochloric, hydrobromic, sulfuric, nitric, acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
  • inorganic or organic acids such as, for instance, hydrochloric, hydrobromic, sulfuric, nitric, acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
  • a preferred class of compounds of the present invention is that wherein, in formula (I):
  • a further object of the present invention is a process for preparing the compounds of formula (I), and the pharmaceutically acceptable salts thereof, which process comprises:
  • Y is hydroxy or a leaving group selected, for instance, from chloro, 2,4,5-trichlorophenoxy, 2,4-dinitro-phenoxy, succinimido-N-oxy, imidazolyl group, and the like.
  • condensation reactions as set forth above under processes (a) and (b) is carried out according to known methods, for instance those described in the aforementioned EP-A-246,868.
  • reaction between a compound of formula (II) or (IV) with a compound of formula (III) is preferably carried out with a molar ratio (II):(III) or (IV):(III) of from 1:1 to 1:2.
  • the reaction is carried out in an organic solvent, such as, dimethylsulphoxide, hexamethylphosphotriamide, dimethylacetamide, dimethylformamide, ethanol, phenyl, or pyridine, in the presence of an organic or inorganic base such as triethylamine, diisopropyl ethylamine, or sodium or potassium carbonate or bicarbonate, and of a condensing agent such as, N-ethyl-N'-(3-dimethylamino-propyl)-carbodiimide, N,N'-dicyclohexyl-carbodiimide, or 1-hydroxy-benzotriazole hydrate.
  • an organic solvent such as, dimethylsulphoxide, hexamethylphosphotriamide, dimethylacetamide, dimethylformamide, ethanol, phenyl, or pyridine
  • an organic or inorganic base such as triethylamine, diisopropyl ethylamine, or sodium or potassium carbon
  • the reaction temperature may vary from about -10°C to about 100°C, and the reaction time from about 1 to about 24 hours.
  • the aforementioned condensation reaction may be carried out in an organic solvent such as, for instance, dimethylformamide, dioxane, pyridine, tetrahydrofurane, or mixtures thereof with water, optionally in the presence of an organic or inorganic base, e.g. N,N'-diisopropylethylamine, triethylamine, sodium or potassium bicarbonate, at a temperature of from about 0°C to about 100°C, and for a time varying from about 2 hours to about 48 hours.
  • an organic solvent such as, for instance, dimethylformamide, dioxane, pyridine, tetrahydrofurane, or mixtures thereof with water
  • an organic or inorganic base e.g. N,N'-diisopropylethylamine, triethylamine, sodium or potassium bicarbonate
  • the reaction of a compound of formula (Ia) with succinic anhydride, as defined in point (vii) above, is preferably carried out with a molar ratio (Ia):succinic anhydride of from 1:1 to 1:3 in an organic solvent such as, for instance, dimethyl sulphoxide or dimethylformamide, and in the presence of an organic or inorganic base such as, e.g., triethylamine, diisopropylethylamine, sodium or potassium carbonate, and the like.
  • the reaction temperature may vary from about 25°C to about 100°C, and the reaction time from about 1 hour to about 12 hours.
  • the reaction with water in an alkaline medium may be carried out according to known methods usually employed for alkaline hydrolysis, for instance by treating the substrate with an excess of sodium or potassium hydroxide in water or in a water/organic solvent admixture, e.g. dioxane, tetrahydrofuran, or acetonitrile, at a temperature of from about 50°C to about 100°C, for a time varying from about 2 hours to about 48 hours.
  • a water/organic solvent admixture e.g. dioxane, tetrahydrofuran, or acetonitrile
  • the compounds of formula (II) are known or may be prepared according to known methods; see, for a reference, Arcamone et al. in Gazzetta Chim. Ital. 97 , 1097 (1967).
  • the compounds of formula (IV) are known compounds as well, for instance as reported in the aforementioned WO 97/28123.
  • Salification of a compound of formula (I), as well as preparation of a free compound starting from a salt, may be carried out by known standard methods.
  • the compounds of formula (I) may be purified by conventional techniques such as, e.g., silica gel or alumina column chromatography, and/or by recrystallisation from an organic solvent such as, e.g., a lower aliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, or dimethylformamide.
  • organic solvent such as, e.g., a lower aliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, or dimethylformamide.
  • the compounds of formula (I) according to the present invention are useful as antineoplastic agents.
  • hypoxia-selective cytotoxic agents hypertriglyceride-selective cytotoxic agents
  • the antineoplastic activity of the compounds was evaluated in vivo against advanced human mammary carcinoma xenograft (MX-1) showing a very good antitumor activity.
  • MX-1 human mammary (originally obtained from NCI, NHI, Bethesda, MD) was transplanted s.c. in athymic mice using 15-20 mg of tumor brei.
  • the tumor model was maintained in vivo in adult female Hsd:athymic nude mice.
  • mice were 4-6 weeks old, weighed 20-25 g and were maintained in cages with paper filter covers; food and bedding were sterilised and water was acidified (pH 2.5-3). All animals were supplied by Harlan Nossan (Italy).
  • the mouse colony was routinely tested monthly for the absence of antibodies to a panel of pathogens including Mouse hepatitis, Sendai Virus and Mycoplasma pulmonis.
  • Drug activity was determined on advanced solid tumors (when tumor mass is > 500 mg); tumor growth was assessed by caliper measurement, and tumor weight was estimated according to Geran.
  • the antitumor effect was determined by comparing tumor weights in the treated group and those of the control group on a given day.
  • the percentage of tumor growth inhibition (%T.I.) was calculated 7 days after the last treatment, according to the following equation: 100-(median tumor weight of treated group/median tumor weight of control group)x100
  • Tumor-free mice 90 days after tumor implant are considered cured mice.
  • Toxicity was evaluated on the basis of the body weight reduction and gross autopsy findings, mainly in terms of reduction of spleen and liver size.
  • the compounds of the invention can be administered to mammals, including humans, through the usual routes, for example, parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally.
  • the dosage depends on age, weight and conditions of the patient and on the administration route.
  • a suitable dosage for administration to adult humans may range from about 0.1 to about 150-200 mg pro dose 1-4 times a day.
  • compositions which comprise a compound of formula (I) as an active principle, in association with one or more pharmaceutically acceptable carrier and/or diluent.
  • compositions of the present invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • solutions for intravenous injection or infusion may contain as a carrier, for example, sterile water or preferably, they may be in the form of sterile aqueous isotonic saline solutions.
  • Suspensions or solutions for intramuscular injections may contain, together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • the active ingredient may be mixed with conventional oleaginous or emulsifying excipients.
  • the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone; disaggregating agents, e.g.
  • starch alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulation.
  • Said pharmaceutical preparations may be manufactured by known techniques, for example by means of mixing, granulating, tabletting, sugar-coating or film-coating processes.
  • the present invention provides a method for treating tumors in a patient in need of it, which comprises administering to said patient a composition of the invention.
  • a further object of the present invention is a combined method for treating cancer or for ameliorating the conditions of mammals, including humans, suffering from cancer, said method comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional antitumor agent, close enough in time and in amounts sufficient to produce a therapeutically useful effect.
  • the present invention also provides products containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional antitumour agent as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.
  • antitumor agent is meant to comprise both a single antitumor drug and “cocktails” i.e. a mixture of such drugs, according to the clinical practice.
  • antitumor agents that can be formulated with a compound of formula (I), or alternatively, can be administered in a combined method of treatment, include doxorubicin, daunomycin, epirubicin, idarubicin, etoposide, fluorouracil, melphalan, cyclophosphamide, 4-demethoxy daunorubicin, bleomycin, vinblastin, and mitomycin, or mixtures thereof.
  • Step I The intermediate 4-(2-hydroxyethyl)thiobenzoic acid
  • Step III The intermediate 4-(2-chloroethyl)sulfinylbenzoic acid
  • Step IV The title compound
  • Step I The intermediate 4-(2-chloroethyl)thiocinnamic acid
  • Step II The intermediate 4-(2-chloroethyl)sulfinylcinnamic acid
  • Tablets each weighing 0.250 g and containing 50 mg of the active substance can be manufactured as follows: Composition for 10,000 tablets 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-(2-chloroethylsulfinyl)phenyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2- 500 g carboxamido]propionamidine hydrochloride Lactose 1.400 g Corn starch 500 g Talc powder 80 g Magnesium stearate 20 g
  • the active substance, lactose and half of the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm mesh size.
  • Corn starch (10 g) was suspended in warm water (90 ml) and the resulting paste was used to granulate the powder. The granulate was dried, comminuted on a sieve of 1.4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate was added, carefully mixed and processed into tablets.
  • Capsules each dosed at 0.200 g and containing 20 mg of the active substance can be prepared as follows: Composition for 500 capsules 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-(2-chloroethylsulfinyl)phenyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2- 10 g carboxamido]propionamidine hydrochloride Lactose 80 g Corn starch 5 g Magnesium stearate 5 g
  • This formulation can be encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g for each capsule.
  • An injectable pharmaceutical composition can be manufactured by dissolving 25 g of 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-(2-chloroethylsulfinyl)phenyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride in sterile propyleneglycol (1000 ml) and sealing ampoules of 1-5 ml.

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Claims (10)

  1. Composé qui est un dérivé de distamycine sulfuré oxydé de formule :
    Figure 00460001
       dans laquelle :
    n est égal à 2, 3 ou 4 ;
    c est égal à 1 ou 2 ;
    A représente une liaison, un groupe alkylène en C1 à C4 ou alcénylène en C2 à C4 ;
    R1 et R2, qui sont identiques ou différents, sont choisis entre l'hydrogène, un groupe alkyle en C1 à C4 facultativement substitué avec un ou plusieurs atomes de fluor, un groupe alkoxy en C1 à C4 ;
    X représente un atome d'halogène ;
    B est choisi entre des groupes :
    Figure 00460002
    Figure 00460003
       dans lesquels R3, R4, R5, R6, R7, R8, R9 et R10, qui sont identiques ou différents, sont choisis entre l'hydrogène et un groupe alkyle en C1 à C4 ; R11 représente l'hydrogène, un groupe alkyle en C1 à C4 ou hydroxy, et m est égal à 0, 1 ou 2 ; ou ses sels pharmaceutiquement acceptables.
  2. Composé suivant la revendication 1, dans lequel R3, R4, R5, R6, R7, R8, R9, R10 et R11 représentent, indépendamment les uns des autres, l'hydrogène, un groupe méthyle ou éthyle.
  3. Composé suivant la revendication 1 ou 2, dans lequel
    n est égal à 3 ;
    c est égal à 1 ;
    A représente une liaison ou un groupe vinylène ;
    R1 et R2, qui sont identiques ou différents, sont choisis entre l'hydrogène, des groupes méthyle, méthoxy et trifluorométhyle ;
    X représente un groupe chloro ou bromo ;
    B est choisi entre des groupes :
    Figure 00470001
    Figure 00470002
       dans lesquels R3, R4, R5, R7, R8, R9, R10 et R11, qui sont identiques ou différents, sont choisis entre l'hydrogène et un groupe méthyle ; R6 représente un atome d'hydrogène ; et m est égal à 0 ou 1 ;
       ou ses sels pharmaceutiquement acceptables.
  4. Composé choisi dans le groupe consistant en :
    3- [1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N-méthylamidine ;
    3- [1-méthyl-4[1-méthyl-4[1-méthyl-4[4- (2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N,N'-diméthylamidine ;
    3- [1-méthyl-4[1-méthyl-4[1-méthyl-4[4- (2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N,N',N'-triméthylamidine ;
    3- [1-méthyl-4[1-méthyl-4[1-méthyl-4[4- (2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N-cyanamidine ;
    3- [1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionamidoxime ;
    3- [1-méthyl-4[1-méthyl-4[1-mé-thyl-4[4-(2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionamide ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N-méthylamide ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionitrile ;
    2- [1-méthyl-4[1-méthyl-4[1-méthyl-4[4- (2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]éthylguanidine ;
    3- [1-méthyl-4[1-méthyl-4[1-méthyl-4[4- (2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N,N-diméthylamine ;
    3- [1-méthyl-4[1-méthyl-4[1-méthyl-4[4- (2-bromoéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[3-méthyl-4-(2-chloroéthyl-sulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)-cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N-méthylamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-propion-N,N'-diméthylamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-propion-N,N,-diméthylamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N-cyanamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-propionamidoxime ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-propionamide ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthyl-sulfinyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-propionamide ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-propionitrile ;
    2-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-éthylguanidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N,N,N'-triméthylamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthyl-sulfonyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-propionamidine ;
    3- [1-méthyl-4 [1-méthyl-4 [1-méthyl-4[4- (2-chloroéthylsulfonyl)phényl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-propion-N-méthylamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthyl-sulfonyl)phényl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N,N'-diméthylamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfonyl)phényl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N-cyanamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfonyl)phényl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-propionamidoxime ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfonyl)phényl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionamide ; 3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionitrile ;
    2-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chlorcéthylsulfinyl)phényl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]éthylguanidine ;
    3- [1-méthyl-4[1-méthyl-4[1-méthyl-4 [4- (2-chloroéthylsulfonyl)-cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionamidine ;
    3- [1-méthyl-4 [1-méthyl-4[1-méthyl-4 [4-(2-chloroéthylsulfonyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N-méthylamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfonyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N,N'-diméthylamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfonyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propion-N-cyanamidine ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfonyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamidol-pyrrole-2-carboxamido]-propionamidoxime ;
    3-[1-méthyl-4[1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfonyl)cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionamide ; 3 - [1-méthyl-4 [1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfonyl)-cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]propionitrile ;
    2- [1-méthyl-4 [1-méthyl-4[1-méthyl-4[4-(2-chloroéthylsulfonyl)-cinnamoyl-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-pyrrole-2-carboxamido]éthylguanidine ; et ses sels pharmaceutiquement acceptables.
  5. Procédé pour la préparation des composés de formule (I) et leurs sels pharmaceutiquement acceptables, procédé qui comprend :
    (a) lorsque B est autre que des groupes
    Figure 00510001
       la réaction d'un composé de formule :
    Figure 00520001
       avec un composé de formule :
    Figure 00520002
       formules dans lesquelles n, c, R1, R2, X et A répondent aux définitions figurant dans la revendication 1, et Y représente un groupe hydroxy ou un groupe portant convenable ;
       de manière à obtenir un composé de formule :
    Figure 00520003
       et ensuite, facultativement, la réaction d'un composé de formule (Ia) avec :
    (i) un composé de formule H2N-(CH2)r-NH2 dans laquelle r est égal à 2 ou 3, de manière à obtenir un composé de formule (I) dans lequel B représente un groupe :
    Figure 00530001
    (ii) un composé de formule H2N-CH2-CHO, de manière à obtenir un composé de formule (I) dans lequel B représente un groupe :
    Figure 00530002
    (iii) un composé de formule H2N-CN, de manière à obtenir un composé de formule (I) dans lequel B représente un groupe :
    Figure 00530003
    (iv) un composé de formule H2N-OR6, de manière à obtenir un composé de formule (I) dans lequel B représente un groupe :
    Figure 00530004
    (v) un composé de formule N2N-NH2, de manière à obtenir un composé de formule (I) dans lequel B représente un groupe :
    Figure 00530005
    (vi) un composé de formule HNR4R5, de manière à obtenir un composé de formule (I) dans lequel B représente un groupe :
    Figure 00540001
       et ensuite, facultativement, avec un composé de formule H2NR3, de manière à obtenir un composé de formule (I) dans lequel B représente un groupe :
    Figure 00540002
    (vii) de l'anhydride succinique, de manière à obtenir un composé de formule (I) dans laquelle B représente un groupe -C≡ N ;
    (viii) de l'eau dans un milieu alcalin, de manière à obtenir un composé de formule (I) dans laquelle B représente un groupe -CONR9R10 dans lequel R9 et R10 représentent l'un et l'autre un atome d'hydrogène ;
    (ix) un composé de formule HNR9R10, de manière à obtenir un composé de formule (I) dans laquelle B représente un groupe :
    Figure 00540003
       et ensuite avec de l'eau dans un milieu alcalin, de manière à obtenir un composé de formule (I) dans laquelle B représente un groupe -CONR9R10, dans lequel R9 et R10 sont tels que définis dans la revendication 1 ; ou
    (b) lorsque B est autre qu'un groupe :
    Figure 00550001
       la réaction d'un composé de formule :
    Figure 00550002
       avec un composé de formule :
    Figure 00550003
       formules dans lesquelles n, c, B, R1, R2, X, Y et A répondent aux définitions précitées ;
       de manière à obtenir le composé correspondant de formule (I) :
       et, si cela est désiré, la conversion du composé de formule (I) en un de ses sels pharmaceutiquement acceptables.
  6. Procédé suivant la revendication 5, dans lequel dans les composés de formule (III), Y représente un groupe hydroxy ou un groupe choisi entre des groupes chloro, 2,4,5-trichlorophénoxy, 2,4-dinitrophénoxy, succinimido-N-oxy et imidazolyle.
  7. Composition pharmaceutique comprenant un ou plusieurs supports et/ou diluants pharmaceutiquement acceptables et, comme principe actif, un composé tel que défini dans la revendication 1.
  8. Composé tel que défini dans la revendication 1, destiné. à être utilisé dans une méthode de traitement de l'organisme humain ou animal par thérapie.
  9. Composé tel que défini dans la revendication 8, destiné à être utilisé comme agent antitumoral.
  10. Utilisation d'un composé tel que défini dans la revendication 1 dans la production d'un médicament destiné à être utilisé comme agent antitumoral.
EP99941465A 1998-07-30 1999-07-21 Derives distamycine sulfures et oxydes, leur procede de preparation et utilisation en tant qu'agents antitumoraux Expired - Lifetime EP1100778B1 (fr)

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PCT/EP1999/005349 WO2000006542A1 (fr) 1998-07-30 1999-07-21 Derives distamycine sulfures et oxydes, leur procede de preparation et utilisation en tant qu'agents antitumoraux

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GB0011059D0 (en) 2000-05-08 2000-06-28 Pharmacia & Upjohn Spa Use of substituted acryloyl distamycin derivatives in the treatment of tumours associated with high levels of glutathione
GB0015447D0 (en) 2000-06-23 2000-08-16 Pharmacia & Upjohn Spa Combined therapy against tumors comprising substituted acryloyl derivates and alkylating agents
GB0015446D0 (en) 2000-06-23 2000-08-16 Pharmacia & Upjohn Spa Combined therapy against tumors comprising substituted acryloyl distamycin derivates,taxanes and/or antimetabolites
GB0016447D0 (en) 2000-07-04 2000-08-23 Pharmacia & Upjohn Spa Process for preparing distamycin derivatives
GB0029004D0 (en) 2000-11-28 2001-01-10 Pharmacia & Upjohn Spa Process for preparing distamycin derivatives
US20030236198A1 (en) 2001-06-13 2003-12-25 Genesoft, Inc. Antipathogenic benzamide compounds
US6969592B2 (en) 2001-09-26 2005-11-29 Pharmacia Italia S.P.A. Method for predicting the sensitivity to chemotherapy
ATE425753T1 (de) 2002-08-02 2009-04-15 Genesoft Pharmaceuticals Inc Biaryl-verbindungen mit antiinfektiver wirkung
EP1562931A2 (fr) 2002-10-25 2005-08-17 Genesoft Pharmaceuticals, Inc. Composes biaryle anti-infectieux
JP2006509027A (ja) 2002-12-10 2006-03-16 オーシェント ファーマシューティカルズ コーポレーション （ピロールカルボキサミド）−（ベンズアミド）−（イミダゾールカルボキサミド）モチーフを有する抗菌化合物

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